Angiogenesis, the formation of new blood vessels from existing ones, is essential to many physiological and pathological processes. Normally, angiogenesis is tightly regulated by pro- and anti-angiogenic factors, but in the case of diseases such as cancer, ocular neovascular diseases, arthritis, and psoriasis, the process can go awry. Folkman, J., Nat. Med., 1:27-31 (1995).
Angiogenesis is believed to play an important role in sustaining inflammatory tissue expansion (pannus) in rheumatoid arthritis (Walsh et al., Arthritis Res., 3:147-153 (2001). In fact, there are a number of diseases known to be associated with deregulated or undesired angiogenesis. See Carmeliet et al., Nature 407:249-257 (2000). Such diseases include, but are not limited to, ocular neovascularisation, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid (or hematopoietic) tumors (such as leukemias and lymphomas). Other diseases associated with undesired angiogenesis will be apparent to those skilled in the art.
Although many signal transduction systems have been implicated in the regulation of angiogenesis, one recently-characterized endothelial cell systems involves the the CD148 receptor tyrosine kinase (also referred to as DEP-1 (density enhanced phosphatase), ECRTP (endothelial cell receptor tyrosine phosphatase), HPTPη, or BYP, depending upon species and cDNA origin).
CD148 is a mammalian transmembrane protein, belonging to a class of endothelial cell surface receptors known as Type III density enhanced receptor protein tyrosine phosphatases (PTP). Protein tyrosine phosphorylation is an essential element in signal transduction pathways which control fundamental cellular processes including growth and differentiation, cell cycle progression, and cytoskeletal function. Binding of a ligand to a receptor protein tyrosin kinase (PTK) catalyzes autophosphorylation of tyrosine residues in the enzyme's target substrates, while binding of a ligand to a receptor PTP catalyzes dephosphorylation. The level of intracellular tyrosine phosphorylation of a target substrate is determined by the balance between PTK and PTP. PTKs play a significant role in promoting cell growth, while PTPs down-regulate the activity of PTKs by inhibiting cell growth. CD148 has been shown to promote differentiation of erythroid progentior cells, modulate lymphocyte function when crosslinked with other signaling proteins, and inhibit clonal expression of breast cancer cell lines overexpressing the protein. Confirming its role as an inhibitor of cell growth, CD148 has also recently been shown to mediate inhibitory signals that block angiogenesis, an essential biological activity necessary for cell migration and proliferation, making CD148 an important target for treatment of cancer by activating CD148 mediated inhibitiion of angiogenesis associated with tumor growth.
Like other receptor protein tyrosine phosphatases, CD148 has an intracellular carboxyl moiety with a catalytic domain, a single transmambrane domain, and an extracellular amino terminal domain (comprising five tandem fibronectin type III (FNIII) repeats, which have a folding pattern similar to that of Ig-like domains). The FNIII domains have an absolute specificity for phosphotyrosine residues, a high affinity for substrate proteins, and a specific activity which is several orders of magnitude greater than that of the PTKs. The FNIII domains are believed to participate in protein/protein interactions to Activation of CD148 triggers autophosphorylation of CD148, which tranduces a biological signal resulting in inhibition of angiogenesis.
U.S. Pat. No. 6,552,169 discloses polynucleotide sequences relating to human DEP-1 (CD148) and polyclonal antibodies generated against polypeptides encoded by the polynucleotides.
U.S. Pat. No. 6,248,327 discloses the role of CD148 in angiogenesis and provides a method of modulating angiogenesis in a mammal by administering compositions that specifically bind to the ectodomain of CD148, and also discloses the use of monoclonal antibodies that specifically bind to an unspecified region of the CD148 ectodomain to activate CD148 anti-angiogenesis activity.
An effective CD148 activation therapy might benefit a vast population of cancer patients because most solid tumors require neovascularization to grow beyond 1-2 millimeters in diameter. Such therapy might have wider application in other angiogenesis-associated diseases as well, such as retinopathies, arthritis, and psoriasis.
There is an undeveloped need to identify new agents that specifically recognize and bind CD148. Such agents would be useful for diagnostic screening and therapeutic intervention in disease states that are associated with CD148 activity.
Accordingly, it is an object of the present invention to provide specific binding agents of CD148 that activate CD148 activity. Such agents of the present invention take the form of antibodies and fragments thereof that specifically bind to CD148 epitopes.
The disclosure all patents, patent applications, and other documents cited herein are hereby expressly incorporated by reference in their entirety.